This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT Acetylcholine (ACh) is involved in brain reward and learning, and changes to ACh may contribute to substance abuse disorders. The reinforcing effects produced by cocaine arise, in part, from release of dopamine (DA) in midbrain dopaminergic neurons. Stimulation of ACh inputs can increase DA release in the nucleus accumbens - a critical brain area involved in the rewarding effects produced by cocaine. ACh-esterase (AChE) inhibitors block cocaine self-administration in monkeys (Wilson and Schuster 1973), block cocaine place preference and locomotor sensitization in mice (Hikida et al. 2003), and block reinstatement induced by exposure to methamphetamine(METH) in rats (Hiranita et al. 2006). Taken together, these data suggest that increasing ACh activity may reduce METH craving in humans. Our lab recently completed a study to determine the effects of the AChE inhibitor rivastigmine on the self-reported subjective effects produced by METH (De La Garza et al. 2008a;De La Garza et al. 2008b)(see also Preliminary Studies). We found that METH (30 mg, IV) administration significantly increased self-reported Desire for METH, and treatment with rivastigmine abolished this response. This finding suggests that further research on this promising class of compounds as treatments for stimulant addiction is warranted. To this end, we propose a double-blind, placebo-controlled, between-groups evaluation of interactions between cocaine and oral rivastigmine and between cocaine and oral huperzine A (HupA). I. HYPOTHESIS 1. Relative to placebo-treated participants, treatment with rivastigmine or HupA will reduce cocaine-induced craving and choices for cocaine. 2. (a)Relative to placebo-treated participants, treatment with rivastigmine or HupA will reduce cocaine-induced increases in heart rate and blood pressure. (b) Relative to placebo-treated participants, treatment with rivastigmine or HupA will not increase the adverse events produced by cocaine. 3. (a) Relative to placebo-treated participants, treatment with rivastigmine, but not HupA, will associated with increased levels of cocaine. (b) Relative to placebo-treated participants, treatment with rivastigmine, but not HupA, will be associated with increased formation of ecgonine and benzoylecgonine, and decreased formation of ecgonine methylester. II. SPECIFIC AIMS 1. Among cocaine-dependent, non-treatment seeking participants, to establish the ability of rivastigmine (3 or 6 mg, daily) or HupA (0.4 or 0.8 mg, daily), as compared to placebo, to reduce cocaine-induced craving (0, 20, and 40 mg, IV) and to reduce reinforcing effects produced by cocaine (20 mg, IV/infusion). 2. To determine the safety of rivastigmine and HupA in cocaine-dependent participants who receive cocaine in a laboratory setting. 3. To determine the effects of AChE inhibition on plasma levels of cocaine and cocaine metabolites. Public Health Significance: Cocaine abuse is an important health problem that is associated with serious medical, psychiatric, social, and economic consequences. No medications are currently available for prevention of relapse in patients who are addicted to cocaine, and compounds such as rivastigmine and HupA are predicted to be useful for this indication. The testing of HupA is particularly exciting since it has antioxidant and neuroprotective properties that may also contribute to its efficacy as a treatment medication for cocaine dependence.